Novel isothiacalothrixin B analogues exhibit cytotoxic activity on human colon cancer cells in vitro by inducing irreversible DNA damage

• Published in: PloS one 2018-09, Vol.13 (9), p.e0202903-e0202903
• Main Authors: Dhatchana Moorthy, Nachiappan, Muthu Ramalingam, Bose, Iqbal, Saleem, Mohanakrishnan, Arasambattu K, Gunasekaran, Krishnasamy, Vellaichamy, Elangovan
• Format: Article
• Language: English
• Subjects: Anticancer properties; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Binding; Biochemistry; Biology and life sciences; Biophysics; Camptothecin; Cancer; Care and treatment; Cell culture; Cell cycle; Cell Cycle Checkpoints - drug effects; Cell Line, Tumor; Cell proliferation; Cell survival; Cell Survival - drug effects; Colon; Colon cancer; Colonic Neoplasms - drug therapy; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Colorectal cancer; Crystallography; Cyclin-dependent kinase inhibitor p21; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Cytotoxic agents; Cytotoxicity; Deoxyribonucleic acid; DNA; DNA damage; DNA Damage - drug effects; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drugs; Flow cytometry; Genetic aspects; GTP-binding protein; Humans; Immunoglobulins; Indole Alkaloids - chemistry; Kinases; Ligands; Lung cancer; Lung diseases; Lymphocytes B; Medicine and Health Sciences; Molecular Docking Simulation; Molecular modelling; Molecular Structure; Organic chemistry; p53 Protein; Physical Sciences; Proteins; Research and Analysis Methods; Sulfur; Time dependence; Toxicity; Transcription activation; Transcription, Genetic - drug effects; Tumor cell lines; Tumors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0202903

Preliminary cytotoxic analysis of sulphur containing isosteric analogues of calothrixin B identified the useful anti-tumour activity of thia/isothiacalothrixin B which necessitated it's biological evaluation in colon and lung cancer cell lines. The isothia analogues induced cytotoxicity of HCT116 in a time-dependent manner and inhibited the clonogenic survival of HCT116 and NCI-H460 cells in a dose-dependent manner comparable to the standard anti-cancer drug camptothecin. Herein employing flow cytometry, we demonstrate that isothiacalothrixin B analogues inhibited proliferation of colon cancer cells by the arrest of cells in S and G2/M phases over a period of 48 hours at a concentration of 5 μM. Our results also suggest that the cytotoxicity of thia analogues of calothrixin B is partially mediated by induction of cellular DNA strand breaks. The UV-Vis spectroscopic studies with CT-DNA revealed groove binding for calothrixin B and its thia analogues wherein subsequent in silico molecular modelling studies indicated preferential binding to the AT-rich regions of minor groove of DNA. Furthermore, thiacalothrixin B caused transcriptional activation of p21waf1/cip1 promoter and upregulation of its protein levels independent of p53. The induction of DNA damage response pathway leads to apoptosis in isothiacalothrixin B but not in thiacalothrixin B treated cells. The isothia analogues SCAB 4 induced DNA strand breaks and cell cycle arrest even after treatment for a short period (i.e., 4 hours) and the cell cycle effects were irreversible. For the first time, this study provides detailed cellular effects on the potential use of isothiacalothrixin B analogues as cytotoxic agents.